Mesenchymal Stem Cell (MSC) regulation of pulmonary macrophage populations in Acute Respiratory Distress Syndrome (ARDS).

间充质干细胞 (MSC) 对急性呼吸窘迫综合征 (ARDS) 中肺巨噬细胞群的调节。

• 批准号: MR/L017229/1
• 负责人: Anna Krasnodembskaya
• 金额: $ 57.42万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL017229%2F1
• 关键词: Mesenchymal; Stem; Cell; MSC; regulation

Acute Respiratory Distress Syndrome (ARDS) is a severe clinical syndrom that affects 20% of all critically ill patients in intensive care. Unfortunately, around 30-50% of these people will die from the condition and the quality of life of the survivers can be seriously reduced due to the consequent chronic lung problems.There is no effective treatments for this condition at this time and therefore new medicines are urgently needed. ARDS is characterised by an excessive and disregulated inflammation in the lung that leads to inappropriate infiltration of immune cells, lungs fill with water and fail to maintain its main function - breathing. In order to breath these patients require mechanical ventilation.ARDS results from multiple causes, although pneumonia induced ARDS is the most common and the most devastating. Inflammation is the way in which the body reacts to infection, irritation or other injury. Normally, inflammation is one way the body heals and copes with the infection, however, when disregulated in certain condition such as ARDS it can lead to severe damages and impair of the the lung function. Immune cells called macrophages have increasingly been recognized to play a key role in the development and resolution of ARDS functioning as a coordinators of inflammatory responses. Recently more and more attention of clinicians and basic scientists working in the field of ARDS research is drawn to cell-based therapies. A key advantage of cell based therapy compared to pharmacologic treatment is that cells can actively respond to the local microenvironment and exert multiple beneficial effects, modulating several injurious and reparative pathways in this complex disease process.One of the most promising candidate for a cell based therapy for ARDS are cells termed Mesenchymal Stem Cells (MSC), which represent one kind of adult stem cells (can be easily isolated from tissues of adult patients or healthy volunteers), because of this there is no ethical issues that are related to use of embryonic tissues. MSC could easily be propagated and manipulated under laboratory conditions and have capacity to differentiate into multiple different cell types of the body. Importantly, long term research has shown their safety in terms of developing tumors.Multiple preclinical animal studies conducted by our group as well as by other investigators showed that MSC indeed have protective effect when administered as a treatment for ARDS. Among several beneficial effects, their administration always is associated with drastically reduced inflammation, however the mechanisms of this phenomenon are still unclear and data on their interaction with the immune cells of the lung remain unsufficient and controversial. To translate MSC into the clinical practice it is essential that we have more precise understanding of their mechanism of action. The main question we are keen to address in the proposed research is: how MSC treatment influence the lung macrophages? What alterations do MSC induce in their functions and what molecular mechanisms mediate those changes.Based on our preliminary data and results from other studies we have reasons to hypothesize that MSC will promote polarization of macrophages towards the state in which they will supress the inflammation and promote the resolution of ARDS- so called "alternatively activated macrophages" or M2 macrophages.The mechanistic data from this study will bring development of new therapy on the MSC basis closer to the patients. Additionally, it will broaden the existing knowledge of lung macrophage biology and their role in the resolution of ARDS which could lead to other new treatments. Importantly, findings from the proposed study may also have relevance for other macrophage dependent inflammatory conditions.

急性呼吸窘迫综合征（ARDS）是一种严重的临床综合征，影响重症监护病患者的20％。不幸的是，由于随之而来的慢性肺部问题，这些人中约有30-50％的人会死于状况，幸存者的生活质量可以大大降低。目前对这种情况没有有效的治疗方法，因此紧急需要新药物。 ARDS的特征是肺部过度且无调炎症，导致免疫细胞的不适当浸润，肺充满水，无法维持其主要功能 - 呼吸。为了呼吸这些患者需要机械通气。炎症是人体对感染，刺激或其他损伤的反应方式。通常，炎症是人体愈合并应对感染的一种方式，但是，当在某些条件下（例如ARDS）不调时，它可能导致严重的损害和肺功能受损。越来越多地认识到称为巨噬细胞的免疫细胞在炎症反应的协调员的发展和解决方案中起关键作用。最近，在ARDS研究领域工作的临床医生和基础科学家的关注越来越多地吸引了基于细胞的疗法。 A key advantage of cell based therapy compared to pharmacologic treatment is that cells can actively respond to the local microenvironment and exert multiple beneficial effects, modulating several injurious and reparative pathways in this complex disease process.One of the most promising candidate for a cell based therapy for ARDS are cells termed Mesenchymal Stem Cells (MSC), which represent one kind of adult stem cells (can be easily isolated from tissues of adult patients or healthy志愿者），因此，没有与胚胎组织使用有关的道德问题。 MSC可以在实验室条件下很容易地传播和操纵，并具有分化为多种不同细胞类型的人体的能力。重要的是，长期的研究表明，它们在发展肿瘤方面的安全性。我们小组以及其他研究人员进行的多个临床前动物研究表明，在用作ARDS治疗时，MSC确实具有保护作用。在几种有益效果中，它们的给药始终与炎症大幅减少有关，但是这种现象的机制仍不清楚，并且数据与它们与肺部免疫细胞相互作用的数据仍然不足和争议。为了将MSC转化为临床实践，我们必须对其作用机理有更精确的了解。我们渴望在拟议的研究中解决的主要问题是：MSC治疗如何影响肺巨噬细胞？ MSC在其功能中诱导哪些变化以及哪些分子机制介导了这些变化。基于我们的初步数据和其他研究的结果，我们有理由假设MSC将促进巨噬细胞极化，以使他们倾向于炎症并促进所谓的“ ARDS ON NEW ON NEW ON GRENATION ON GRENATION ON GRENATION ON GRENATION ON GRENATION ON GRENATION ON GRENATION of ARTIAPTY ONTAINTY ON tHE THE WARNICATION”，从而从事“或Mocrophages”的发展。 MSC基础更接近患者。此外，它将扩大对肺巨噬细胞生物学的现有知识及其在解决ARDS解决中的作用，这可能导致其他新疗法。重要的是，拟议的研究的发现也可能与其他巨噬细胞依赖的炎症条件相关。

项目成果

P47 Hypercapnia impairs the ability of mesenchymal stem cells to promote distal lung epithelial wound repair in ards

P47 高碳酸血症损害间充质干细胞促进ARDS远端肺上皮伤口修复的能力

• DOI: 10.1136/thoraxjnl-2017-210983.189
• 发表时间: 2017
• 作者: Fergie N

Repair of Acute Respiratory Distress Syndrome in COVID-19 by Stromal Cell Administration (REALIST-COVID) Phase 2 Randomised Controlled Trial

通过基质细胞管理修复 COVID-19 中的急性呼吸窘迫综合征 (REALIST-COVID) 第 2 期随机对照试验

• DOI: 10.1164/ajrccm-conference.2022.205.1_meetingabstracts.a5285
• 发表时间: 2022
• 作者: Gorman E

Effects of hypercapnic acidosis on the primary cells relevant to ARDS pathophysiology and the therapeutic potential of mesenchymal stem cells

高碳酸血症对ARDS病理生理学相关原代细胞的影响和间充质干细胞的治疗潜力

• DOI: 10.1183/1393003.congress-2017.pa341
• 发表时间: 2017
• 作者: Fergie N

Differential effects of the cystic fibrosis lung inflammatory environment on mesenchymal stromal cells.

• DOI: 10.1152/ajplung.00218.2020
• 发表时间: 2020-12-01
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Abreu SC;Hampton TH;Hoffman E;Dearborn J;Ashare A;Singh Sidhu K;Matthews DE;McKenna DH;Amiel E;Barua J;Krasnodembskaya A;English K;Mahon B;Dos Santos C;Cruz FF;Chambers DC;Liu KD;Matthay MA;Cramer RA;Stanton BA;Rocco PRM;Wargo MJ;Weiss DJ;Rolandsson Enes S
• 通讯作者: Rolandsson Enes S

Multicomponent Peptide Hydrogels as an Innovative Platform for Cell-Based Tissue Engineering in the Dental Pulp.

• DOI: 10.3390/pharmaceutics13101575
• 发表时间: 2021-09-28
• 期刊: Pharmaceutics
• 影响因子: 5.4
• 作者: Afami ME;El Karim I;About I;Krasnodembskaya AD;Laverty G;Lundy FT
• 通讯作者: Lundy FT